Daniel O'Connell, the CEO. Thank you very much for coming. We appreciate it.
Thanks, Andrew. Thanks for having us.
So maybe the best place to start is just broadly, you know, in getting people up to speed, introducing people to the company for those with less familiarity, and then we'll go into specific questions.
Sure. So, Acumen Pharmaceuticals is a publicly traded, clinical stage biopharmaceutical company, which the founding science underpinning our program, sabirnetug, is focused on Aβ oligomers, which are a pathogenic form of Aβ that is an early and persistent factor in the pathophysiology of Alzheimer's disease. And we are at present, we've completed a Phase I last year that read out, with encouraging results we can discuss this morning and have launched a Phase II, what we're calling the ALTITUDE-AD study for sabirnetug in early Alzheimer's patients.
So we're really looking to address with a novel treatment option that large unmet need in the early Alzheimer's population, and doing it through a mechanism that we think is differentiated by way of our focus and targeting of Aβ oligomers.
I guess, you know, why specifically, you know, oligomeric Aβ, in terms of, you know, the most sensible path to pursue an AD treatment?
Sure, Andrew. So, a couple decades of research has helped inform sort of the complexity of Aβ biology and really, reinforce the notion that these soluble aggregates of the Aβ peptide, commonly referred to as Aβ oligomers, really are a distinct species, and they're, and importantly, are distinctly toxic. So if you look at, research on Aβ monomers, just a single, monomeric unit, monomers do not have, intrinsic toxic properties. I mean, in fact, some will argue that it has a trophic or protective, physiological role. Amyloid plaques, the hallmark, pathological hallmark of the disease, really represent, an end state of the aggregated form of, of Aβ and other, protein aggregates. Plaques also are not, intrinsically toxic to, to neurons.
In contrast to that, if you look at, again, it's a couple of decades of research at labs throughout the world, demonstrating that oligomers, a variety of different oligomers of various sizes, have a propensity to bind to neurons at synapses and induce things like tau hyperphosphorylation, disrupt circuit function. So, long-term potentiation is a mechanism of neuronal integrity and synaptic function. And so these oligomers really are commonly referred to as the toxic species. And I think we have had a variety of different interventions in Alzheimer's disease that have tried to sort of find ways to generate clinical benefit. But to our view, none has been principally originated and directed towards oligomers such as sabirnetug is.
That's very helpful. I guess, in the context of the INTERCEPT-AD results, you know, the level of validation they provided, you know, how they differ from what some other companies have shown, and maybe how they inform things going forward.
Sure. So, a great question, and you know, we couldn't have been more excited about the Phase I results from INTERCEPT-AD. So this was a Phase I study, exclusively in early AD population. So everyone in the study had pathology or amyloid pathology confirmed. It was a single ascending dose and multiple ascending dose design, with some overlap between the SAD and MAD. We evaluated a range of doses from as low as 2 mg per kg, upwards of 60 mg per kg. And really, the proof of mechanism study was intended to confirm safety, principally, sort of the... and really with a focus on ARIA and the dosing window. Target engagement, and we'll come back to this 'cause that was an important novel finding for the INTERCEPT-AD study.
And then we were also looking at kind of the standard clinical and biomarker effects, both imaging on amyloid PET as well as cerebrospinal fluid and plasma biomarker effects. And you know, the readout of the study, which was presented initial top-line results, was at the AAIC meeting in Amsterdam last July. We've had a subsequent kind of rollout of some of the fluid biomarker effects, and I think very convincingly to us, we've established a competitive safety profile, inclusive of the ARIA. We saw a dose-response on target engagement, which has helped inform dose selection for Phase II. And you know, much to our surprise and encouragement, we saw effects both on the imaging and fluid biomarkers.
And those included a reduction in the amyloid PET signal at the high dose levels that was sort of in line or consistent with what we've seen for Leqembi, even with just... This is 3 administrations, so this is a very short duration study, really, you know, principally a safety study, but we had all these biomarker effects, so we're pretty excited about that. And the other CSF and plasma, we saw sort of a you know, the confluence of effects on the Aβ 42- 40 ratio, phospho-tau 181 and in cerebrospinal fluid, and then a couple of synaptic markers, neurogranin, which is a postsynaptic marker, moving in the right direction at the high dose levels, and then VAMP2, another presynaptic marker, moving in the actually significant across the MAD dose cohorts.
So as we think about oligomer toxicity being mediated through, you know, synaptic disruption and, tau hyperphosphorylation, we, you know, the results, particularly on the fluid biomarker side, reinforce this notion of having an agent such as, sabirnetug, that engages target in a quantifiable fashion and then has these downstream, effects on, known, pathology associated with Alzheimer's disease. So this really gives us, a lot of enthusiasm and confidence in, now the Phase II study, ALTITUDE-AD.
... And then maybe you can just also just tie in, the safety profile in the context of potential therapeutic index.
Sure. So, the safety profile, you know, the primary concern in treating Alzheimer's with anti-Aβ agents is ARIA-E. So this is an imaging observation that can be asymptomatic or symptomatic, and there's great concern, and duly so, for symptomatic cases. I think there is a recognition that little or no ARIA is the treatment objective. And in our study, we had five total cases of ARIA-E out of the 48 subjects that were exposed to drug. We had three at the high cohorts, so 60 mg per kg. Only one of those three was symptomatic, relatively benign, and self-resolved within a matter of weeks. There were two other cases observed, asymptomatic. One was at 10, and one was at 25 mg per kg.
So this, to us, gives us confidence that at the right dose levels, and potentially in even the APOE4 homozygote population, sabirnetug should have a competitive safety profile. We would need to do a longer duration study. We need, you know, more, you know, bigger, you know, chronic dosing. But in the case of ARIA, it's typically one of these early dosing intervals that is subject to an ARIA event. So that's. I mean, that, that, to us, is part of the enthusiasm for why sabirnetug, even if it is a, you know... If it can be a safer agent, it certainly is going to demand the attention of patients and prescribers. Mm.
I should also mention that in the E4 homozygotes, we had 6 E4 homozygotes, none of which had ARIA-E, which is kind of an observation, something curious, given that, the E4 homozygotes, which have, I think, 12-14-fold elevated risk of having disease, also with these other agents, Leqembi and donanemab, have much higher rates of ARIA. Roughly, you know, 30% with Leqembi and upwards of 45%, I think, for donanemab.
And you also touched upon your ability to show target engagement in the data. So maybe you can speak a little bit about the assay and, you know, the significance of the binding data you generated.
Sure. So a little bit, a little bit of background, I mean, more background maybe even, on the programming. So, sabirnetug was developed through a research license in collaboration with Merck & Co. And Merck did some of the, the seminal preclinical work profiling what, they referred to as, 193, what we had termed ACU193, and now which is, referred to as sabirnetug. In some of the Merck, preclinical workup, they established a target engagement assay in the transgenic mice. So they wanted to, to confirm the, the biochemical binding of, sabirnetug 193, in these transgenic mice. And as, as part of that, they developed an ELISA-based assay to basically pull down the complex of the, the drug bound to, oligomers, from brain homogenate.
And so that was sort of a conceptual design that we tasked the team at Acumen to develop a CSF-based target engagement assay that would allow us to measure the complex of sabirnetug bound to oligomers. And as a consequence of a variety of different capture and detection pairings of various antibodies, some proprietary to Acumen and some just sort of commercially available, the team came up with a really robust and sensitive design that allowed us to take patient samples and establish target engagement, even in the single. So it was below the signal, the level of threshold of detection in the 2 mg per kg SAD dose cohort. But as soon as we had single dose at 10, at 25 and 60, you could see target engagement being observed.
Then, as we moved to the MAD dose cohorts, we saw significance across those levels. An important element of the target engagement assay as well was at the higher doses. So, as you achieve sort of higher concentrations of drug exposure, we were not observing, you know, we sort of see a ceiling effect or a plateau in terms of the complex signal that established, which helps reinforce the notion that we don't need to go higher, right? Like, one of the questions going into the Phase I was, well, what if, you know, it just keeps moving up and it's linear? That doesn't really give you a dosing decision or information to think about Phase II.
What we've done since the end of INTERCEPT-AD in preparation for the recently launched ALTITUDE-AD study is model out all these PK/PD scenarios and look for target engagement, you know, using... I think in Phase II, we'll now use 50 mg/kg and 35 mg/kg, which at peak and trough m ranges give us robust target engagement based on the modeling.
It's very helpful. I guess, you know, in the context of having the results in hand, and some recently announced licensing deals in the space, you know, what are your thoughts on the path forward at this point?
... Yeah, I mean, the path forward for us is very clear. We want to generate a compelling proof of concept result in Phase II . You know, a result that could satisfy registration requirements as part of a subsequent confirmatory Phase III . I'm not precisely sure which licensing deals, if you're talking about the AC Immune and, uh-
and Takeda license, I mean, that's for an active vaccination, and I think that's sort of a different treatment paradigm that's gonna involve a lot of time and capital to further establish the safety and clinical benefit. So we think the passive immunization with anti-Aβ agents, you know, we have first-generation products approved with Leqembi and aducanumab. We would anticipate, you know, reasonable likelihood of donanemab receiving approval, and that's gonna establish sort of the treatment paradigm. The infrastructure for those products will be in place, and what we're in pursuit of is a differentiated treatment paradigm with sabirnetug, showing, you know, ideally, better efficacy and safety as a consequence of our mechanism and the unique attributes of sabirnetug.
I guess, you know, in the—from a timeline perspective, you know, how are you thinking about the timeline for ALTITUDE-AD? You know, how are you thinking—what you're thinking about the... maybe talk to people about the trial design, and how confident are you in the-
Yeah.
the N number?
Yeah, let's get to some of the details on ALTITUDE-AD. So this is a Phase II study with two active arms, 180 subjects per cohort, so a fairly robust Phase II design. We're looking at, as I mentioned, the 50 mg per kg, Q4w, and 35 mg per kilogram, Q4w. Each of those doses, we believe, has the possibility of generating clinical benefit. We, I think we are curious to see if they differentiate in terms of the ARIA rates and safety and, potentially some of the biomarker effects. So all of that is gonna help inform what the Phase III plan will be.
The study is employing an 18-month primary outcome, which we're using the iADRS, which is the composite score of cognition and function that Lilly has employed in TRAILBLAZER-ALZ 2. We do have an open-label extension of 12 months subsequent to the primary readout, and we announced the week before last, first patient dosed. There's been a lot of activity getting the study operational. We're really excited about the level of activity at sites and sort of generally the enthusiasm for the study. And, you know, we are—we have not guided to particular readout time frame, but at least as we sit here today, very encouraged at the level of engagement, sites, investigators, and participants. And we'll see how that, you know, how that shakes out.
I can also mention, Andrew, we will launch a Phase I healthy volunteer subcu study in the middle part of the year. That's on track, as well, and that'll give us a little bit of data and information as to where and how we might push forward on a subcu version of sabirnetug. You know, we take the view that subcu is a complementary, you know, form of administration to the IV and think that IV and subcu will actually, for our drug and presumably others, will coexist in a way to satisfy, you know, patient convenience and physician prescribing choices or preferences.
Sort of an initial dose and then a maintenance.
There's a lot of induction versus induction, then maintenance, and I think, those, those are likely to be the, the future state of getting early Alzheimer's patients onto, onto therapy. You know, maybe the induction phase being IV, where there's a, you know, eyes on the patient at a, in a clinical setting, and then, migrating towards a, a more convenient, subcu option.
Are there any inherent challenges to making a subcutaneous version of ACU193?
Well, I mean, I think I don't know that they're inherent. I mean, we are using relatively large weight-based dosing in our, in our IV formulation. We're doing formulation work now for higher concentration formulations, which we think can help with, the, administration of subcu. We also established, late last year, a collaboration and license with Halozyme, which has a, a, an enzyme that allows for, the delivery or injection of large molecules in a subcutaneous format. So we're, we're looking at all of those ways to sort of figure out the, the, the target product profile, such that sabirnetug subcu would be, you know, advantageous and, and competitive and convenient for, for patients.
I mean, the company's been very focused to date, to its success and credit. I guess, you know, at some point, is there thought of, you know, expanding the pipeline, or how are you thinking about that?
Yeah, thanks, Andrew. So, I think, you know, going back to the... you know, we—the company came public in 2021. It was really on the weight of the preclinical evidence and the unmet need in this patient population. You know, the objective of that raise or the capital deployed in the IPO was to run the Phase I and generate proof of mechanism results. And I think what we have observed is that these are very compelling Phase I proof of mechanism results. The board and the current shareholders are very enthusiastic about the de-risking that's been achieved right now and really want to see the results of the Phase II. So yes, I think we kind of continue to...
You know, we, we have maintained a lens or an openness to doing other things, but in terms of being judicious about capital allocation and resources, we're pretty laser focused on executing the sabirnetug program for the foreseeable future.
Interesting. Good. I mean, are there, you know... I guess, as we think about the macro environment in AD, are there any particular aspects that have the most direct read-through to you guys, do you think?
Well, I think in terms of in the Aβ space, you know, we are, sabirnetug ALTITUDE-AD is arguably the next efficacy readout in the, in the Alzheimer's kind of pipeline. You know, we're gonna be observant about, you know, things like TREM2 and, and tau, and think that those mechanisms, should they be clinically validated, such as Aβ, you know, could be complementary, right? I think we're all, right now, those of us that have been in the field for many years, believe that this is not a disease that's going to have a single bullet that's widely applicable to the large population. It's likely to be, in the future, we have the ability to stratify and segment the population and identify which agent or agents are most amenable to that clinical benefit or patient benefit.
So those, I mean, I think it's, you know, it would be great to see more success from some of these other mechanisms. I think that would give the broader population, you know, some confidence that the science is actually yielding, you know, progress and success, and ultimately, that will translate into a better way to address, again, this, you know, big area of unmet need.
Great. I think we're exactly on the time limit. So thank you very much.
Thank you, Andrew.
Thanks for speaking.
Really enjoyed it. Thank you.